The important biological roles that peptides play as hormones enzyme inhibitors, substrates, neurotransmitters, and neuromediators has led to the widespread use of peptides in medicinal chemistry as therapeutic agents. Through binding to receptors or enzymes, peptides Marc are able to influence cell-cell communication and control vital cell functions such as metabolism, immune defense and reproduction. (Babine et al., Chem. Rev. 1997, 97, 1359) Unfortunately, the utility of peptides as drugs is severely limited by several factors, including their rapid degradation by peptidases under physiological conditions, their poor cell permeability, and their lack of binding specificity resulting from conformational flexibility.
In response to these unfavorable characteristics of peptide drugs, many research groups have developed strategies for the design and synthesis of chemical compounds, known as “peptidomimetics”, in which sensitive peptide moieties are removed and replaced with more robust functionalities. In particular, researchers have sought to improve peptide stability and cell permeability by replacing the amide functionality with groups such as hydroxyethylene, (E)-alkenes, carba groups and phosphonamide groups (Gante, J., Angew. Chem. Int. Ed. Engl. 1994, 33, 1699–1720, and references cited therein).
In most cases, these peptidomimetic compounds have been prepared one at a time. A few researchers have also attempted to design combinatorial strategies to produce peptidomimetic libraries (Boger, D, WO 96/03424; Ellman, J., U.S. Pat. No. 5,545,568; Simon. R. et al., Proc. Natl. Acad. Sci. USA 1992, 89, 9367; Bartlett et al.,i Proc. Natl. Acad. Sci. USA 1992, 89, 9367). Unfortunately, these efforts are often limited by lack of stereochemical complexity and control, and/or by restricted ability to substitute base molecules. Also, existing peptidomimetic strategies generally rely on a fixed structure to mimic the peptide bond, and do not allow subsequent modification and diversification of this structure.
There remains a need to develop a synthetic strategy capable of producing complex. highly diversified libraries of compounds that can act as peptidomimetics. There is a particular need for methods and compounds that allow significant stereochemical control and functional group diversity in the production of such libraries. Furthermore, because of the importance of stereochemical complexity in the synthesis of these and other libraries, there also remains a need for the development of stereodiverse compounds and libraries of compounds.